Enabling Safer Paracetamol

First marketed in the US in 1953, paracetamol (acetaminophen) is one of the most widely used drugs in Western society, both in over-the-counter (OTC) products and as a component of prescription medicines. Effective in relieving pain and fever, paracetamol is noted for the absence of gastro-intestinal side-effects at therapeutic doses in contrast to the non-steroidal anti-inflammatory drugs. Exceeding the recommended dose of paracetamol (typically 4000mg daily for adults), however, can cause liver damage. Adverse events range from minor changes in liver enzymes to acute liver failure and, in some cases, death.

The toxicity is not due to paracetamol itself, but a reactive metabolite, NAPQI. paracetamol metabolismparacetamol scp-1 scp-123 structureNormally, NAPQI is rapidly de-toxified by conjugation with glutathione, but the pathway can become saturated as a result of overdose, combination with alcohol, or in individuals with polymorphisms in the P450 metabolizing enzymes. Inadvertent overdose can occur through combination of OTC products with prescription medicines.

In recent years, analogues of paracetamol with reduced potential for hepatic toxicity, such as the saccharin derivative, SCP-1, have been described. SCP-1 is rapidly metabolized to SCP-123, which is believed to be responsible for efficacy. Development of such analogues has been hampered by the lack of a cost-effective synthesis, but Louisiana chemists have now described a viable route to SCP-123. The synthesis comprises three steps from commercially available starting materials, requires no chromatographic purification and is amenable to large-scale processing. Full details are published in Organic Process Research & Development.

Sweet Synthesis – Automated Carbohydrate Production

Starchy FoodsAlthough carbohydrates were previously thought of as little more than an energy source, it is now recognised that they play a key role in many biochemical processes including intercellular recognition, immune function, fertilisation and certain types of cancer. From a synthetic viewpoint, the structural complexity that makes carbohydrates important in so many biological processes poses significant challenges. Unlike oligonucleotides and peptides, carbohydrates can form branched as well as linear structures, and there are a staggering number of ways in which monosaccharides can be combined. Increasingly powerful and versatile methods have been developed to allow the synthesis of pure oligosaccharides in the laboratory, but the process requires regioselective protection of hydroxyl groups as well as stereoselective assembly of glycosidic linkages and is technically difficult and very time consuming. Speaking at the annual meeting of the American Chemical Society in Salt Lake City, Dr Peter H Seeberger has described the development of a fully automated carbohydrate synthesiser that should make complex carbohydrates more accessible. A simple cleavage, deprotection and purification protocol provides rapid access to naturally occurring and synthetic oligosaccharides and is suitable for use by non-experts.

artist impression of malaria parasites bursting from red blood cellsOne application that Seeberger’s group have been addressing with the new technology is the development of a vaccine against malaria. Fatalities caused by the malaria parasite, Plasmodium falciparum, are thought to result, at least in part, from a reaction to the malaria toxin, glycosylphosphatidylinositol (GPI). Anti-GPI vaccination was found to protect against fatality in mice and clinical trials of an anti-toxin vaccine to protect against the inflammation and anaemia associated with malarial infection are scheduled for 2010 in Mozambique and Tanzania. Seeberger also believes that carbohydrate-based vaccines could be used against other serious infectious diseases, including antibiotic-resistant infections and HIV.